tbuckley/cabot-search huggingface dataset:
Primary prophylaxis for spontaneous bacterial peritonitis is linked to antibiotic resistance in the Veterans Health Administration
Authors: Bryan D. Badal, Scott Silvey, Lyuba Dragilev, Jacqueline G. O’Leary, Timothy R. Morgan, Ramsey Cheung, Arpan Patel, Shari Rogal, Heather Patton, Anna Nobbe, Sofia S. Jakab, Jinze Liu, Nilang Patel, Jasmohan S. Bajaj
Journal: Hepatology (2023)

Spontaneous bacterial peritonitis (SBP) is a major cause of mortality. Although SBP primary prophylaxis (SBPPr) with fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX) is often used, resistance could reduce its benefit. Aim: Analyze peritoneal fluid resistance patterns in patients with a first SBP episode with/without SBPPr using the Veterans Health Administration corporate data warehouse and to evaluate national antibiograms. Corporate data warehouse data were extracted using validated International Classification of Disease-9/10 codes, culture, resistance data, and outcomes of 7553 patients who developed their first inpatient SBP between 2009 and 2019 and compared between those with/without SBPPr. Escherichia coli ( E. coli ) and Klebsiella pneumoniae ( K. pneumoniae ) sensitivity to ciprofloxacin and TMP-SMX was calculated using 2021 Veterans Health Administration antibiogram data from all states. The most common isolates were E. coli , K. pneumoniae , and Staphylococcus species. Veterans taking ciprofloxacin SBBPr had higher fluoroquinolone resistance (34% vs 14% no SBPPr, p &lt;0.0001); those taking TMP-SMX had higher TMP-SMX resistance (40% vs 14%, p &lt;0.0001). SBPPr patients showed higher culture positivity, greater length of stay, higher second SBP, and higher probability of liver transplant rates versus no SBPPr. Multivariable models showed SBBPr to be the only variable associated with gram-negative resistance, and SBPPr was associated with a trend toward longer length of stay. E. coli ciprofloxacin sensitivity rates were 50%–87% and 43%–92% for TMP-SMX. K. pneumoniae ciprofloxacin sensitivity was 76%–100% and 72%–100% for TMP-SMX. Conclusion: Among patients who developed their first SBP episode, there was a higher prevalence of antibiotic resistance in those on SBPPr, with a high rate of fluoroquinolone resistance across the Veterans Health Administration sites.
Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures
Authors: Kandarp M. Dave, Donna B. Stolz, Venugopal R. Venna, Victoria A. Quaicoe, Michael E. Maniskas, Michael John Reynolds, Riyan Babidhan, Duncan X. Dobbins, Maura N. Farinelli, Abigail Sullivan, Tarun N. Bhatia, Hannah Yankello, Rohan Reddy, Younsoo Bae, Rehana K. Leak, Sruti S. Shiva, Louise D. McCullough, Devika S. Manickam
Journal: Journal of Controlled Release (2023)
Examining the interim proposal for name change to steatotic liver disease in the US population
Authors: Cheng Han Ng, Kai En Chan, Mark Muthiah, Caitlyn Tan, Phoebe Tay, Wen Hui Lim, Darren Jun Hao Tan, Clarissa Elysia Fu, Jie Ning Yong, Zhen Yu Wong, Benjamin Koh, Nicholas WS Chew, Nicholas Syn, Daniel Q. Huang, Yock Young Dan, Mohammad S. Siddiqui, Arun J. Sanyal, Mazen Noureddin
Journal: Hepatology (2023)

Fatty liver is the commonest liver condition globally and traditionally associated with NAFLD. A consensus meeting was held in Chicago to explore various terminologies. Herein, we explore the proposed changes in nomenclature in a population data set from the US.Statistical analysis was conducted using survey-weighted analysis. Assessment of fatty liver was conducted with vibration-controlled transient elastography. A controlled attenuation parameter of 288 dB/m was used to identify hepatic steatosis. Patients were classified into nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease. Liver stiffness measures at ≥8.8, ≥11.7, and ≥14 kPa were used to identify clinically significant fibrosis, advanced fibrosis, and cirrhosis, respectively. A total of 5102 individuals were included in the analysis. Using a survey-weighted analysis, a total of 25.43%, 6.95%, and 0.73% of the population were classified as nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, respectively. A sensitivity analysis at controlled attenuation parameter of 248 dB/m and fatty liver index found similar distribution. In a comparison between nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, there was no significant difference between the odds of advanced fibrosis and cirrhosis between groups. However, viral hepatitis steatotic liver disease individuals were found to have a significantly higher odds of clinically significant fibrosis (OR: 3.76, 95% CI, 1.27-11.14, p =0.02) compared with nonalcoholic steatotic liver disease.The current analysis assessed the proposed changes based on discussions from the consensus meeting. Although the definitions are an interim analysis of discussions, steatotic liver disease respects the underlying liver etiology and reduces stigma while increasing awareness of FL among viral and alcohol-associated steatosis/steatohepatitis.
5S rRNA pseudogene transcripts are associated with interferon production and inflammatory responses in alcohol-associated hepatitis
Authors: Jianguo Wu, Adam Kim, Xiaoqin Wu, Semanti Ray, Daniela S. Allende, Nicole Welch, Annette Bellar, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E. Nagy
Journal: Hepatology (2023)

Background and Aims: Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH. Approach and Results: Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver diseases, were positively correlated with certain RNA5SP transcripts. Real-time quantitative PCR demonstrated that RNA5SP transcripts were upregulated in peripheral blood mononuclear cells (PBMCs) from patients with sAH. In sAH livers, increased 5S rRNA and reduced nuclear MAF1 (MAF1 homolog, negative regulator of RNA polymerase III) protein suggested a higher activity of RNA polymerase III (Pol III); inhibition of Pol III reduced RNA5SP expression in monocytic THP-1 cells. Expression of several RNA5SP transcript-interacting proteins was downregulated in sAH, potentially unmasking transcripts to immunosensors. Indeed, siRNA knockdown of interacting proteins potentiated the immunostimulatory activity of RNA5SP transcripts. Molecular interaction and cell viability assays demonstrated that RNA5SP transcripts adopted Z-conformation and contributed to ZBP1-mediated caspase-independent cell death. Conclusions: Increased expression and binding availability of RNA5SP transcripts was associated with hepatic IFN production and inflammation in sAH. These data identify RNA5SP transcripts as a potential target to mitigate inflammation and hepatocellular injury in AH.
Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy
Authors: Dominick J. Hellen, Ashley Bennett, Sudarshan Malla, Caroline Klindt, Anuradha Rao, Paul A. Dawson, Saul J. Karpen
Journal: Hepatology (2023)

Background and Aims: A recent multicenter genetic exploration of the biliary atresia splenic malformation syndrome identified mutations in the ciliary gene PKD1L1 as candidate etiologic contributors. We hypothesized that deletion of Pkd1l1 in developing hepatoblasts would lead to cholangiopathy in mice. Approach and Results: CRISPR-based genome editing inserted loxP sites flanking exon 8 of the murine Pkd1l1 gene. Pkd1l1 Fl/Fl cross-bred with alpha-fetoprotein-Cre expressing mice to generate a liver-specific intrahepatic Pkd1l1 -deficient model (LKO). From embryonic day 18 through week 30, control ( Fl/Fl ) and LKO mice were evaluated with standard serum chemistries and liver histology. At select ages, tissues were analyzed using RNA sequencing, immunofluorescence, and electron microscopy with a focus on biliary structures, peribiliary inflammation, and fibrosis. Bile duct ligation for 5 days of Fl/Fl and LKO mice was followed by standard serum and liver analytics. Histological analyses from perinatal ages revealed delayed biliary maturation and reduced primary cilia, with progressive cholangiocyte proliferation, peribiliary fibroinflammation, and arterial hypertrophy evident in 7- to 16-week-old LKO versus Fl/Fl livers. Following bile duct ligation, cholangiocyte proliferation, peribiliary fibroinflammation, and necrosis were increased in LKO compared with Fl/Fl livers. Conclusions: Bile duct ligation of the Pkd1l1 -deficient mouse model mirrors several aspects of the intrahepatic pathophysiology of biliary atresia in humans including bile duct dysmorphogenesis, peribiliary fibroinflammation, hepatic arteriopathy, and ciliopathy. This first genetically linked model of biliary atresia, the Pkd1l1 LKO mouse, may allow researchers a means to develop a deeper understanding of the pathophysiology of this serious and perplexing disorder, including the opportunity to identify rational therapeutic targets.
Nanotechnology based drug delivery systems for the treatment of anterior segment eye diseases
Authors: Adaeze Linda Onugwu, Chinekwu Sherridan Nwagwu, Obinna Sabastine Onugwu, Adaeze Chidiebere Echezona, Chinazom Precious Agbo, Stella Amarachi Ihim, Prosper Emeh, Petra Obioma Nnamani, Anthony Amaechi Attama, Vitaliy V. Khutoryanskiy
Journal: Journal of Controlled Release (2023)

Diseases affecting the anterior segment of the eye are the primary causes of vision impairment and blindness globally. Drug administration through the topical ocular route is widely accepted because of its user/patient friendliness - ease of administration and convenience. However, it remains a significant challenge to efficiently deliver drugs to the eye through this route because of various structural and physiological constraints that restrict the distribution of therapeutic molecules into the ocular tissues. The bioavailability of topically applied ocular medications such as eye drops is typically less than 5%. Developing novel delivery systems to increase the retention time on the ocular surfaces and permeation through the cornea is one of the approaches adopted to boost the bioavailability of topically administered medications. Drug delivery systems based on nanotechnology such as micelles, nanosuspensions, nanoparticles, nanoemulsions, liposomes, dendrimers, niosomes, cubosomes and nanowafers have been investigated as effective alternatives to conventional ocular delivery systems in treating diseases of the anterior segment of the eye. This review discussed different nanotechnology-based delivery systems that are currently investigated for treating and managing diseases affecting the anterior ocular tissues. We also looked at the challenges in translating these systems into clinical use and the prospects of nanocarriers as a vehicle for the delivery of phytoactive compounds to the anterior segment of the eye.
Effect of allogeneic adipose tissue‐derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction – the <scp>SCIENCE</scp> trial
Authors: Abbas Ali Qayyum, Bas van Klarenbosch, Sabina Frljak, Andraz Cerar, Gregor Poglajen, Denise Traxler‐Weidenauer, Pawel Nadrowski, Christina Paitazoglou, Bojan Vrtovec, Martin W. Bergmann, Steven A. J. Chamuleau, Wojtek Wojakowski, Mariann Gyöngyösi, Adriaan Kraaijeveld, Kristian Schultz Hansen, Karsten Vrangbæk, Erik Jørgensen, Steffen Helqvist, Francis Richard Joshi, Ellen Mønsted Johansen, Bjarke Follin, Morten Juhl, Lisbeth Drozd Højgaard, Anders Bruun Mathiasen, Annette Ekblond, Mandana Haack‐Sørensen, Jens Kastrup
Journal: European Journal of Heart Failure (2023)

The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF).The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0 ml, p = 0.736) and LVEF (-1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups.The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.
Effective behaviour change techniques for family and close friends: A systematic review and meta-analysis across the addictions
Authors: S.S. Merkouris, S.N. Rodda, S.R. Aarsman, D.C. Hodgins, N.A. Dowling
Journal: Clinical Psychology Review (2023)

This systematic review aimed to determine whether the use of specific behaviour change technique (BCT) groups are associated with greater effectiveness for psychosocial interventions delivered to family and close friends (FCFs) impacted by addiction. A systematic search of peer-reviewed and grey literature published until August 2021 identified 32 studies in 38 articles. An established BCT taxonomy (93 BCTs clustered into 16 groups) was adapted (inclusion of seven additional BCT groups) and applied to 57 interventions. The meta-analyses indicated that some, but not all, FCF outcomes were improved by the exclusion of BCTs within several groups (Reward and Threat, Scheduled Consequences, Confrontation of the Addicted Person to Engage in Treatment, and Goals and Planning) and inclusion of BCTs within the Restoring a Balanced Lifestyle group. Addicted person outcomes were improved by the inclusion of some BCTs within several groups (Repetition and Substitution, Reward and Threat, Scheduled Consequences, and Restoring a Balanced Lifestyle). Relationship functioning outcomes were improved by the inclusion of BCTs within the Confrontation of the Addicted Person to Engage in Treatment group. Future research involving the development and evaluation of numerous interventions or comprehensive multi-component interventions that can address the various needs of FCFs, without counteracting them, is required.
Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Authors: L.E. Hendriks, K.M. Kerr, J. Menis, T.S. Mok, U. Nestle, A. Passaro, S. Peters, D. Planchard, E.F. Smit, B.J. Solomon, G. Veronesi, M. Reck
Journal: Annals of Oncology (2023)
Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers
Authors: Juan Jin, Yuhao Xie, Jin-Shi Zhang, Jing-Quan Wang, Shi-Jie Dai, Wen-fang He, Shou-Ye Li, Charles R. Ashby, Zhe-Sheng Chen, Qiang He
Journal: Drug Resistance Updates (2023)

Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment option for RCC due to the lack of significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used to treat gastrointestinal tumors and renal cell carcinoma, inhibits the tyrosine kinase activity of a number of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, rearranged during transfection (RET) and fms-related receptor tyrosine kinase 3 (Flt3). Although sunitinib has been shown to be efficacious in the treatment of patients with advanced RCC, a significant number of patients have primary resistance to sunitinib or acquired drug resistance within the 6–15 months of therapy. Thus, in order to develop more efficacious and long-lasting treatment strategies for patients with advanced RCC, it will be crucial to ascertain how to overcome sunitinib resistance that is produced by various drug resistance mechanisms. In this review, we discuss: 1) molecular mechanisms of sunitinib resistance; 2) strategies to overcome sunitinib resistance and 3) potential predictive biomarkers of sunitinib resistance.
IL‐13, periostin and dipeptidyl‐peptidase‐4 reveal endotype‐phenotype associations in atopic dermatitis
Authors: Laura Maintz, Thomas Welchowski, Nadine Herrmann, Juliette Brauer, Claudia Traidl‐Hoffmann, Regina Havenith, Svenja Müller, Claudio Rhyner, Anita Dreher, Matthias Schmid, Thomas Bieber
Journal: Allergy (2023)

The heterogeneous (endo)phenotypes of atopic dermatitis (AD) require precision medicine. Currently, systemic therapy is recommended to patients with an Eczema Area and Severity Index (EASI)≥16. Previous studies have demonstrated an improved treatment response to the anti-interleukin (IL)-13 antibody tralokinumab in AD subgroups with elevated levels of the IL-13-related biomarkers dipeptidyl-peptidase (DPP)-4 and periostin.
Enhanced RNA knockdown efficiency with engineered fusion guide RNAs that function with both CRISPR-CasRx and hammerhead ribozyme
Authors: Yonghao Zhan, Congcong Cao, Aolin Li, Hongbing Mei, Yuchen Liu
Journal: Genome biology (2023)

Abstract Background CRISPR-Cas13 is a newly emerging RNA knockdown technology that is comparable to RNAi. Among all members of Cas13, CasRx degrades RNA in human cells with high precision and effectiveness. However, it remains unclear whether the efficiency of this technology can be further improved and applied to gene therapy. Results In this study, we fuse CasRx crRNA with an antisense ribozyme to construct a synthetic fusion guide RNA that can interact with both CasRx protein and ribozyme and tested the ability of this approach in RNA knockdown and cancer gene therapy. We show that the CasRx-crRNA-ribozyme system (CCRS) is more efficient for RNA knockdown of mRNAs and non-coding RNAs than conventional methods, including CasRx, shRNA, and ribozyme. In particular, CCRS is more effective than wild-type CasRx when targeting multiple transcripts simultaneously. We next use bladder cancer as a model to evaluate the anticancer effects of CCRS targeting multiple genes in vitro and in vivo. CCRS shows a higher anticancer effect than conventional methods, consistent with the gene knockdown results. Conclusions Thus, our study demonstrates that CCRS expands the design ideas and RNA knockdown capabilities of Cas13 technology and has the potential to be used in disease treatment.
Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation
Authors: Qin Jin, Xiaoyi Liu, Zhenpeng Zhuang, Jiayuan Huang, Shixue Gou, Hui Shi, Yu Zhao, Zhen Ouyang, Zhaoming Liu, Lei Li, Junjie Mao, Weikai Ge, Fangbing Chen, Manya Yu, Yezhi Guan, Yinghua Ye, Chengcheng Tang, Ren Huang, Kepin Wang, Liangxue Lai
Journal: Genome biology (2023)

CRISPR-based toolkits have dramatically increased the ease of genome and epigenome editing. SpCas9 is the most widely used nuclease. However, the difficulty of delivering SpCas9 and inability to modulate its expression in vivo hinder its widespread adoption in large animals.
KIN: a method to infer relatedness from low-coverage ancient DNA
Authors: Divyaratan Popli, Stéphane Peyrégne, Benjamin M. Peter
Journal: Genome biology (2023)

Abstract Genetic kinship of ancient individuals can provide insights into their culture and social hierarchy, and is relevant for downstream genetic analyses. However, estimating relatedness from ancient DNA is difficult due to low-coverage, ascertainment bias, or contamination from various sources. Here, we present KIN, a method to estimate the relatedness of a pair of individuals from the identical-by-descent segments they share. KIN accurately classifies up to 3rd-degree relatives using at least 0.05x sequence coverage and differentiates siblings from parent-child pairs. It incorporates additional models to adjust for contamination and detect inbreeding, which improves classification accuracy.
A pH-dependent anti-CD47 antibody that selectively targets solid tumors and improves therapeutic efficacy and safety
Authors: Yulu Li, Juan Liu, Wei Chen, Wei Wang, Fang Yang, Ximing Liu, Yao Sheng, Kaixin Du, Miaomiao He, Xueyuan Lyu, Huiyu Li, Linlin Zhao, Zhizhong Wei, Fengchao Wang, Sanduo Zheng, Jianhua Sui
Journal: Journal of Hematology & Oncology (2023)

Abstract Background The antiphagocytic molecule CD47 is overexpressed in a wide variety of cancer cells, and antibodies targeting CD47 for cancer therapies are currently under intensive investigation. However, owing to the ubiquitous expression of CD47 on healthy cells, anti-CD47 therapies often achieve only weak therapeutic benefits and can induce severe side effects. Here, we report the generation of a pH-dependent anti-CD47 antibody (BC31M4) which selectively binds to tumors under the acidic solid tumor microenvironment. Methods BC31M4 was generated using antibody phage display and a pH-dependent selection strategy. The pH-dependent binding and blocking activities of BC31M4 were verified using in vitro assays, and the structural basis of the pH-dependent binding property was characterized. BC31M4’s antitumor effect was confirmed by both phagocytosis assays and studies in xenograft models. The tumor selectivity, mechanism of action, PK properties, side effects, and therapeutic efficacy were further evaluated in humanized (hCD47 and its receptor hSIRPα) immunocompetent syngeneic mouse models. Results The crystal structure reveals that two histidines locate within the CDRs of the light chain directly contribute to the pH-dependent binding of BC31M4. BC31M4 promotes macrophage phagocytosis of tumor cells more potently at acidic-pH than at physiological-pH. Our hCD47/hSIRPα humanized syngeneic mouse model results demonstrated that BC31M4 selectively accumulates in tumors but not in normal tissues. BC31M4 causes minimal side effects and exhibits superior PK properties as compared to the other examined anti-CD47 antibodies. When combined with adoptive T cell transfer, BC31M4 efficiently promotes adaptive immune responses against tumors and also induces immune memory. Moreover, we show that BC31M4’s antitumor effects rely on an Fc that mediates strong effector functions. Conclusions Our study illustrates that the development of a tumor-selective, pH-dependent anti-CD47 antibody safely confers strong therapeutic effects against solid tumors, thus providing a promising therapeutic strategy to overcome the challenges of anti-CD47 therapy.